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Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses.

ABSTRACT: After the emergence of pandemic influenza viruses in 1957, 1968, and 2009, existing seasonal viruses were observed to be replaced in the human population by the novel pandemic strains. We have previously hypothesized that the replacement of seasonal strains was mediated, in part, by a population-scale boost in antibodies specific for conserved regions of the hemagglutinin stalk and the viral neuraminidase. Numerous recent studies have shown the role of stalk-specific antibodies in neutralization of influenza viruses; the finding that stalk antibodies can effectively neutralize virus alters the existing dogma that influenza virus neutralization is mediated solely by antibodies that react with the globular head of the viral hemagglutinin. The present study explores the possibility that stalk-specific antibodies were boosted by infection with the 2009 H1N1 pandemic virus and that those antibodies could have contributed to the disappearance of existing seasonal H1N1 influenza virus strains. To study stalk-specific antibodies, we have developed chimeric hemagglutinin constructs that enable the measurement of antibodies that bind the hemagglutinin protein and neutralize virus but do not have hemagglutination inhibition activity. Using these chimeric hemagglutinin reagents, we show that infection with the 2009 pandemic H1N1 virus elicited a boost in titer of virus-neutralizing antibodies directed against the hemagglutinin stalk. In addition, we describe assays that can be used to measure influenza virus-neutralizing antibodies that are not detected in the traditional hemagglutination inhibition assay.

SUBMITTER: Pica N

PROVIDER: S-EPMC3289326 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses.

Pica Natalie N Hai Rong R Krammer Florian F Wang Taia T TT Maamary Jad J Eggink Dirk D Tan Gene S GS Krause Jens C JC Moran Thomas T Stein Cheryl R CR Banach David D Wrammert Jens J Belshe Robert B RB García-Sastre Adolfo A Palese Peter P

Proceedings of the National Academy of Sciences of the United States of America 20120130 7

After the emergence of pandemic influenza viruses in 1957, 1968, and 2009, existing seasonal viruses were observed to be replaced in the human population by the novel pandemic strains. We have previously hypothesized that the replacement of seasonal strains was mediated, in part, by a population-scale boost in antibodies specific for conserved regions of the hemagglutinin stalk and the viral neuraminidase. Numerous recent studies have shown the role of stalk-specific antibodies in neutralization ...[more]

PMID: 22308500

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Project description:Commercial influenza virus vaccines often elicit strain-specific immune responses and have difficulties preventing illness caused by antigenically drifted viral variants. In the last 20 years, the H3N2 component of the annual vaccine has been updated nearly twice as often as the H1N1 component, and in 2019, a mismatch between the wild-type (WT) H3N2 vaccine strain and circulating H3N2 influenza strains led to a vaccine efficacy of ∼9%. Modern methods of developing computationally optimized broadly reactive antigens (COBRAs) for H3N2 influenza viruses utilize current viral surveillance information to design more broadly reactive vaccine antigens. Here, 7 new recombinant hemagglutinin (rHA) H3 COBRA hemagglutinin (HA) antigens were evaluated in mice. Subsequently, two candidates, J4 and NG2, were selected for further testing in influenza-preimmune animals based on their ability to elicit broadly reactive antibodies against antigenically drifted H3N2 viral isolates. In the preimmune model, monovalent formulations of J4 and NG2 elicited broadly reactive antibodies against recently circulating H3N2 influenza viruses from 2019. Bivalent mixtures of COBRA H1 and H3 rHA, Y2 + J4, and Y2 + NG2 outperformed multiple WT H1+H3 bivalent rHA mixtures by eliciting seroprotective antibodies against H1N1 and H3N2 isolates from 2009 to 2019. Overall, the newly generated COBRA HA antigens, namely, Y2, J4, and NG2, had the ability to induce broadly reactive antibodies in influenza-naive and preimmune animals in both monovalent and bivalent formulations, and these antigens outperformed H1 and H3 WT rHA vaccine antigens by eliciting seroprotective antibodies against panels of antigenically drifted historical H1N1 and H3N2 vaccine strains from 2009 to 2019. IMPORTANCE Standard-of-care influenza virus vaccines are composed of a mixture of antigens from different influenza viral subtypes. For the first time, lead COBRA H1 and H3 HA antigens, formulated as a bivalent vaccine, have been investigated in animals with preexisting immunity to influenza viruses. The cocktail of COBRA HA antigens elicited more broadly reactive anti-HA antibodies than those elicited by a comparator bivalent wild-type HA vaccine against H1 and H3 influenza viruses isolated between 2009 and 2019.

Project description:Reassortment of gene segments between coinfecting influenza A viruses (IAVs) facilitates viral diversification and has a significant epidemiological impact on seasonal and pandemic influenza. Since 1977, human IAVs of H1N1 and H3N2 subtypes have cocirculated with relatively few documented cases of reassortment. We evaluated the potential for viruses of the 2009 pandemic H1N1 (pH1N1) and seasonal H3N2 lineages to reassort under experimental conditions. Results of heterologous coinfections with pH1N1 and H3N2 viruses were compared to those obtained following coinfection with homologous, genetically tagged, pH1N1 viruses as a control. High genotype diversity was observed among progeny of both coinfections; however, diversity was more limited following heterologous coinfection. Pairwise analysis of genotype patterns revealed that homologous reassortment was random while heterologous reassortment was characterized by specific biases. pH1N1/H3N2 reassortant genotypes produced under single-cycle coinfection conditions showed a strong preference for homologous PB2-PA combinations and general preferences for the H3N2 NA, pH1N1 M, and H3N2 PB2 except when paired with the pH1N1 PA or NP. Multicycle coinfection results corroborated these findings and revealed an additional preference for the H3N2 HA. Segment compatibility was further investigated by measuring chimeric polymerase activity and growth of selected reassortants in human tracheobronchial epithelial cells. In guinea pigs inoculated with a mixture of viruses, parental H3N2 viruses dominated but reassortants also infected and transmitted to cage mates. Taken together, our results indicate that strong intrinsic barriers to reassortment between seasonal H3N2 and pH1N1 viruses are few but that the reassortants formed are attenuated relative to parental strains.IMPORTANCE The genome of IAV is relatively simple, comprising eight RNA segments, each of which typically encodes one or two proteins. Each viral protein carries out multiple functions in coordination with other viral components and the machinery of the cell. When two IAVs coinfect a cell, they can exchange genes through reassortment. The resultant progeny viruses often suffer fitness defects due to suboptimal interactions among divergent viral components. The genetic diversity generated through reassortment can facilitate the emergence of novel outbreak strains. Thus, it is important to understand the efficiency of reassortment and the factors that limit its potential. The research described here offers new tools for studying reassortment between two strains of interest and applies those tools to viruses of the 2009 pandemic H1N1 and seasonal H3N2 lineages, which currently cocirculate in humans and therefore have the potential to give rise to novel epidemic strains.

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Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses.

Publications

Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses.

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